I . DNA & RNA | 4. The role of genetic variations in the pathogenesis of diseases; methods to study genetic factors

Question 1

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
1. What is the difference between the genomes of two unrelated people?

Answer 1

The difference between the genomes of two unrelated people is around 0,1% - max 0,5% (3 million base pairs), meaning your genome is almost 99,5% similar to any other person.

Question 2

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
2. What is the consequence of genetic variations?

Answer 2

The consequence of these variations are the phenotype (height, hair color, skin color, etc.), diseases, risk factor for illnesses and many other things => monogenic disorder

Question 3

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
3. What is monogenic disorder caused by?

Answer 3

Monogenic disorder are caused by a variation in a single gene (sickle cell anemia, cystic fibrosis, Huntington disease)

Question 4

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
4. What are the causes of differences between individuals ?

Answer 4

Causes of differences between individuals include independent assortment, the exchange of genes (crossing over and recombination) during meiosis and various mutational events.

Question 5

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
5. What are the definition and features of BASE CHANGE?

Answer 5

Base change: modification of a single nucleotide (can be insertion/deletion, but usually a substitution)
- Responsible for 0,1/0,5% of the difference between two unrelated individuals => affects alleles

Question 6

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
6. What are the definition and features of LENGTH CHANGE?

Answer 6

Length variation: a change in more than one nucleotide
- There can be 0 copies or several hundred of them
- 0,4/0,5% if the difference between two unrelated individuals => affects alleles

Question 7

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
7. What is SNP (polymorphism)?

Answer 7

SNP (polymorphism) = single base change occurs in a population at a frequency of 1% or higher

Question 8

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
8. What is Point mutation?

Answer 8

single base change occurs in less than 1% of a population

Question 9

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
9A. What are Length variations that are polymorphisms?

Answer 9

1. Microsatellites
2. Variable number of tandem repeats (minisatellites)
3. Copy number variations (CNV)

Question 10

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES - Length variations that are polymorphisms
9B. What are Microsatellites?

Answer 10

The length of the repeated block is between 2-10 bp long

Question 11

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES - Length variations that are polymorphisms
9B. What are Variable number of tandem
repeats (minisatellites)?

Answer 11

length of the repeated block is between 10- 100/1000 bp long

Question 12

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES - Length variations that are polymorphisms
9C. What are Copy number variations (CNV)?

Answer 12

length of the repeated block is extremely long; 10,000 – 100,000 bp

Question 13

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
10A. What is the difference between mutation and polymorphism?

Answer 13

Mutation usually results in diseases, while polymorphisms (SNP for example) either increase or decrease the risk of a certain disease.

Question 14

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
10B. Mutation usually results in diseases, while polymorphisms (SNP for example) either increase or decrease the risk of a certain disease.
=> Give an example?

Answer 14

Ccystic fibrosis is the result of a mutation in a single gene for the CFTR protein, which normally acts as a channel that allows cells to release chloride and other ions, but when defective (as in CF), it results in impaired salt balance and production of thick mucus (no water transported).

Question 15

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
11. What are Possible effects of SNPs and point mutations (in coding regions)?

Answer 15

• Nothing (biological effect  mRNA stability)
• False splicing (introns cutting)
• Change of one amino acid
• Nonsense mutation (premature stop)

Question 16

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
12. What are Possible effects of insertions or deletions (in coding regions):

Answer 16

Frame-shift mutation

Question 17

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
13. What are Possible effects of length variations (in coding regions)?

Answer 17

• 3n bps: n amino acids
• 3n+1, or 3n+1 bps: frame-shift mutation

Question 18

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
14. What are Possible effects of genetic variations in non-coding regions?

Answer 18

Alternation of the binding affinity of transcription factors, micro-RNA molecules etc.

Question 19

I. ROLE OF GENETIC VARIATIONS IN PATHOGENESIS OF DISEASES
15. Describe Etiology of disease

Answer 19

• 100% heritability: completely due to genetic factors (monogenic disorders)
• 0% heritability: completely due to environmental factors (but no such thing really exists)
• Complex diseases: many gene variations and environmental factors both contribute to the disease (malignant tumors, diabetes, cardiovascular diseases)

Question 20

II. METHODS TO STUDY GENETIC FACTORS
1. What are the 4 methods to study genetic factors?

Answer 20

1. Candidate gene analysis
2. GWAS (genome wide association study)
3. Case-control study
4. Transmission disequilibrium test

Question 21

II. METHODS TO STUDY GENETIC FACTORS
2. What are the features of candidate gene analysis?

Answer 21

• One commonly used technique to identify genetic risk factors for complex disorders such as alcoholism is the candidate gene approach, which directly tests the effects of genetic variants of a potentially contributing gene in an association study.
• A hypothesis is set up surrounding selected genes
• Specific targets are analyzed
• Sometimes, important target may be omitted

Question 22

II. METHODS TO STUDY GENETIC FACTORS
3. What is GWAS (genome wide association study)?

Answer 22

• Genome-wide association studies (GWAS) help scientists identify genes associated with a particular disease (or another trait).
• This method studies the entire set of DNA (the genome) of a large group of people, searching for small variations, called single nucleotide polymorphisms or SNPs (pronounced “snips”).
• Polymorphisms everywhere in the genome/whole genome
• No hypothesis => just investigate everything and look for
  some connection
• Statistical analysis provides correction for multiple testing

Question 23

II. METHODS TO STUDY GENETIC FACTORS
3. What is Case-control study?

Answer 23

• Allele or genotype frequencies of two groups (case and control) are compared to see if statistically significant differences can be observed

Question 24

II. METHODS TO STUDY GENETIC FACTORS
4. What is Transmission disequilibrium test?

Answer 24

• Affected/ill children are studied to see which allele they get from each parent => only heterozygote parents can be included in the study
• If there is a monogenic disorder => all the children studied will be affected and in 100% of them, they will have gotten the gene from either their mother or father